Abiraterone prodrugs

Abstract

Sustained-release abiraterone prodrug formulations, methods, and kits for parenteral administration to a subject having a sex hormone-dependent benign or malignant disorder such as prostate cancer, a syndrome due to androgen excess, and/or a syndrome due to glucocorticoid excess such as hypercortisolemia.

1 . A method of treating or preventing a disease or disorder in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a substantially pure compound of Formula I, or a pharmaceutically acceptable salt thereof, dispersed or dissolved in a pharmaceutically acceptable carrier, 
       
         
           
           
               
               
           
         
         wherein R 1  is R 10 , O—R 10 , or NHR 10 , 
         wherein R 10  is selected from: 
         a C 7-30  alkyl; a C 7-30  alkenyl; a C 7-30  alkynyl; an alkyl substituted with a cycloalkyl, which has a total number of carbons between 5 and 16; an alkyl substituted with a phenyl, which has a total number of carbons between 7 and 16; a cycloalkyl optionally substituted with one or more alkyl, which has a total number of carbons between 5 and 16; and 
       
       
         
           
           
               
               
           
         
         wherein the disease or disorder is selected from a sex hormone-dependent benign or malignant disorder, a syndrome due to androgen excess, and a syndrome due to glucocorticoid excess. 
       
     
     
         2 . The method of  claim 1 , wherein the substantially pure compound of Formula I is characterized as having a purity by weight of at least 95%, preferably, at least 98%, such as about 98.5%, about 99%, about 99.5%, or higher. 
     
     
         3 . The method of  claim 1 , wherein the substantially pure compound of Formula I is characterized as having less than 1% by weight of a corresponding ethyl prasterone derivative having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The method of  claim 1 , wherein the substantially pure compound of Formula I is a substantially pure abiraterone decanoate having the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The method of  claim 4 , wherein the substantially pure abiraterone decanoate is characterized as having less than 1% (e.g., less than 0.5% by weight, such as less than 0.3%, less than 0.2%, or less than 0.1%) by weight of ethyl prasterone decanoate having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The method of  claim 4 , wherein the substantially pure abiraterone decanoate is characterized as having no detectable amount of ethyl prasterone decanoate. 
     
     
         7 . The method of  claim 1 , wherein the pharmaceutically acceptable carrier comprises a pharmaceutically acceptable oil and optionally a further pharmaceutically acceptable solvent. 
     
     
         8 . (canceled) 
     
     
         9 . The method of  claim 7 , wherein the pharmaceutically acceptable oil is selected from vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil, and soybean oil, and the further pharmaceutically acceptable solvent, if present, comprises benzyl alcohol, benzyl benzoate, or a combination thereof. 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . The method of  claim 1 , wherein the pharmaceutical composition is characterized as (1) having a viscosity of less than 0.1 Pa*s, such as about 0.05 Ps*s or lower; (2) having a glide force of about 5-15 N when measured using a 23 G, 1.5 inch needle, and/or about 30-150 N when measured using a 27 G, 1.5 inch needle; (3) having no more than 1000 particles having a size of 10 μm or greater, and no more than 300 particles having a size of 25 μm or greater, when measured according to USP <788> and/or <789>; and/or (4) having less than 100 EU/ml, such as less than 25 EU/ml of bacterial endotoxins measured according to USP <85>. 
     
     
         13 .- 17 . (canceled) 
     
     
         18 . The method of  claim 1 , wherein the disease or disorder is selected from prostate cancer, breast cancer, ovarian cancer, bladder cancer, hepatocellular carcinoma, lung cancer, endometriosis, polycystic ovary syndrome, Cushing's syndrome, Cushing's disease, classical or nonclassical congenital adrenal hyperplasia, precocious puberty, hirsutism, and combinations thereof. 
     
     
         19 . The method of  claim 1 , wherein the disease or disorder is prostate cancer. 
     
     
         20 . The method of  claim 19 , wherein (1) the subject having prostate cancer is characterized as having a rising amount of prostate specific antigen, e.g., following radical prostatectomy; (2) the prostate cancer is a localized prostate cancer, e.g., a high risk localized prostate cancer; (3) the prostate cancer is a metastatic castration-sensitive prostate cancer, non-metastatic castration-sensitive prostate cancer, non-metastatic castration-resistant prostate cancer, or metastatic castration-resistant prostate cancer; (4) the prostate cancer is a newly diagnosed high risk metastatic hormone sensitive prostate cancer; (5) the prostate cancer is a metastatic castration resistant prostate cancer (mCRPC), wherein the subject is asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated; (6) the prostate cancer is a metastatic castration resistant prostate cancer (mCRPC), wherein the subject's disease has progressed on or after a docetaxel-based chemotherapy regimen; or (7) the prostate cancer is a refractory prostate cancer. 
     
     
         21 .- 26 . (canceled) 
     
     
         27 . The method of  claim 1 , further comprising (1) treating the subject with radiotherapy or surgery; (2) administering to the subject one or more other agents selected from anticancer agents, hormone ablation agents, anti-androgen agents, differentiating agents, anti-neoplastic agents, kinase inhibitors, anti-metabolite agents, alkylating agents, antibiotic agents, immunological agents, interferon-type agents, intercalating agents, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, mitotic inhibitors, matrix metalloprotease inhibitors, genetic therapeutics, or combinations thereof; (3) administering to the subject one or more other agents selected from a chemotherapeutic drug, hormone replacement drug, or hormone ablation drug; or (4) treating the subject with an androgen deprivation therapy. 
     
     
         28 .- 30 . (canceled) 
     
     
         31 . The method of  claim 19 , wherein (a) the subject is administered one or more agents selected from hydrocortisone, prednisone, prednisolone, methylprednisolone, and dexamethasone; (b) the subject is administered a poly ADP ribose polymerase (PARP) inhibitor, e.g., niraparib, rucaparib, olaparib, talazoparib, veliparib, and fluzoparib; (c) the subject is administered a gonadotropin-releasing hormone (GnRH) agonist, such as buserelin, leuprolide, deslorelin, fertirelin, histrelin, gonadorelin, lecirelin, goserelin, nafarelin, peforelin or triptorelin, and/or a GnRH antagonist, such as abarelix, cetrorelix, degarelix, ganirelix, elagolix, linzagolixa, or relugolix; (d) the subject is administered a 1 st -generation androgen receptor antagonist, e.g., proxalutamide, bicalutamide, flutamide, nilutamide, topilutamide; (e) the subject is administered a 2 nd -generation androgen receptor antagonist (e.g., apalutamide, darolutamide or enzalutamide); (f) the subject is administered a 3 rd  generation androgen receptor antagonist (such as an N-terminal domain inhibitor) or an androgen receptor degrader molecule, alone or in combination with one or more 1 st  generation or 2 nd  generation androgen receptor antagonists; (g) the subject is administered a chemotherapeutic agent, such as a taxane based chemotherapeutic agent (e.g., docetaxel, cabazitaxel, paclitaxel, etc.) or platinum based chemotherapeutic agent (e.g., cisplatin, carboplatin, oxaliplatin, etc.); (h) the subject is treated with radiotherapy e.g., stereotactic body radiotherapy, neutron radiation; (i) the subject is administered Radium-223; (j) the subject is administered an immunotherapy, such as administering Sipuleucel-T, an immune checkpoint inhibitors (e.g., anti-PD-1 antibody such as pembrolizumab or nivolumab, or anti-PD-L1 antibody such as avelumab or atezolizumab), or an anti-CTLA-4 antibody (e.g., ipilimumab); (k) the subject is administered a kinase inhibitor, e.g., sunitinib, dasatinib, cabozantinib, erdafitinib, dovitinib, capivasertib, onvansertib, ipatasertib, afuresertib, alisertib, apitolisib, opaganib; (l) the subject is administered a therapeutic agent selected from 1) an anti-IL23 targeting monoclonal antibody, e.g., tildrakizumab; 2) a selenium, such as sodium selenite; 3) an EZH2 inhibitor, e.g., CPI-1205, GSK2816126, or tazemetostat; 4) a CDK4/6 inhibitor, e.g., palbociclib, ribociclib, abemaciclib; 6) a bromodomain and extra-terminal domain (BET) inhibitor, e.g., CCS1477, INCB057643, alobresib, ZEN-3694, or molibresib (GSK525762); 7) an anti-CD105 antibody, e.g., TRC105 or carotuximab; 8) niclosamide; 9) an A2A receptor antagonist, e.g., AZD4635; 10) a PI3K inhibitor, e.g., AZD-8186, buparlisib, or dactolisib; 11) a further non-steroidal CYP17A1 inhibitor, e.g. seviteronel; 12) an antiprogestogen, e.g., onapristone; 13) navitoclax; 14) an HSP90 inhibitor, e.g., onalespib (AT13387); 15) an HSP27 inhibitor, e.g., OGX-427; 16) a 5-alpha-reductase inhibitor, e.g., dutasteride; 17) metformin; 18) AMG-386; 19) dextromethorphan; 20) theophylline; 21) hydroxychloroquine; and 22) lenalidomide; or (m) the subject is administered one or more kinase modulators selected from FLT-3 (FMS-like tyrosine kinase) inhibitors, AXL (anexelekto) inhibitors (e.g., Gilteritinib), CDK (cyclin dependent kinase) inhibitors, such as CDK1, 2, 4, 5, 6, 7, or 9 inhibitors, retinoblastoma (Rb) inhibitors, protein kinase B (AKT) inhibitors, SRC inhibitors, IkappaB kinase 1 (IKK1) inhibitors, PIM-1 modulators, Lemur tyrosine kinase 2 (LMTK2) modulators, Lyn inhibitors, Aurora A inhibitors, ANPK (A nuclear protein kinase) inhibitors, extracellular-signal regulated kinase (ERK) modulators, c-jun N-terminal kinase (JNK) modulators, Big MAP kinase (BMK) modulators, p38 mitogen-activated protein kinases (MAPK) modulators, and combinations thereof. 
     
     
         32 .- 44 . (canceled) 
     
     
         45 . The method of  claim 19 , wherein the subject is chemotherapy naïve or hormone therapy naïve prior to being administered the pharmaceutical composition. 
     
     
         46 . The method of  claim 1 , wherein the disease or disorder is breast cancer, e.g., molecular apocrine HER2-negative breast cancer, metastatic breast cancer, such as ER+ metastatic breast cancer, ER+ and HER2 negative breast cancer, AR+ triple negative breast cancer, etc.; or the disease or disorder is associated with 21-hydroxylase deficiency. 
     
     
         47 . (canceled) 
     
     
         48 . (canceled) 
     
     
         49 . The method of  claim 1 , wherein the pharmaceutical composition is administered to the subject via an intramuscular injection, intradermal injection, or subcutaneous injection; and/or the pharmaceutical composition is administered to the subject with or without food. 
     
     
         50 . The method of  claim 1 , wherein the pharmaceutical composition is administered to the subject once a week or once in more than a week. 
     
     
         51 .- 53 . (canceled) 
     
     
         54 . A substantially pure abiraterone decanoate having the following formula: 
       
         
           
           
               
               
           
         
         characterized as having a purity by weight of at least 95%. 
       
     
     
         55 . A method of preparing a pharmaceutical composition, comprising mixing a substantially pure abiraterone decanoate having the following formula: 
       
         
           
           
               
               
           
         
         with a pharmaceutically acceptable carrier, wherein the substantially pure abiraterone decanoate is characterized as having a purity by weight of at least 95%.